Prostate Cancer is the most common malignancy and the second leading cause of cancer death in males in the United States (1). Despite advances in localized therapy of prostate cancer, a significant fraction of men develop metastatic disease at some point in the course of the illness. We have previously studied treatment approaches for this disease which focus on the nuclear matrix and the DNA replication complex. This protocol will continue those studies using the topoisomerase I inhibitor irinotecan (CPT-11) in combination with estramustine.